Involvement of cAMP Signaling Mediators, Epac1, Epac2 and Rap1 in Decidualization of Rat Uterus

Presentation Number: SUN-0032
Date of Presentation: June 22nd, 2014

Mikihiro Yoshie*1, Kazuya Kusama1, Kazuhiro Tamura1, Takiko Daikoku2, Tsutomu Takarada1 and Eiichi Tachikawa1
1Tokyo University of Pharmacy & Life Sciences, Tokyo, Japan, 2Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Abstract

Embryo implantation and appropriate differentiation of uterine stromal cells (ESCs) into decidual cells are crucial events for the establishment of successful pregnancy in the rodent and human. We previously reported that activation of a cAMP signaling mediator, exchange protein directly activated by cAMP (EPAC), promotes ovarian steroid- or cAMP analog-induced decidualization in cultured human ESCs. In addition, siRNA-mediated knock-down of the EPAC subtypes, EPAC1 and EPAC2, or of Rap1, a downstream factor of EPAC signaling, abrogated functional and morphological decidualization of human ESCs. However, whether Epac and Rap1 play roles in decidualization has not been examined in vivo. In the present study, we showed that Epac1, Epac2 and Rap1 expression was up-regulated in decidual cells at implantation sites in pregnant rats. To examine whether the uterine expression of Epac1, Epac2 and Rap1 is associated with embryo implantation and decidualization, a delayed implantation model was used. In the progesterone-primed delayed implantation uterus, Epac1, Epac2 and Rap1 expression was up-regulated in decidual cells at the initiation of implantation induced by treatment with estradiol. However, any effects of estradiol and/or progesterone on the expression of Epac1, Epac2 and Rap1 were minor in ovariectomized non-pregnant rat. We used artificially induced decidualization model to explore the association of Epac1, Epac2 and Rap1 expression with decidualization. The expression of Epac1, Epac2 and Rap1 was enhanced during artificially induced decidualization in the pseudopregnant rat uterus. We further examined the functional roles of these factors during decidualization using an in vitro decidualization model. Treatment of cultured rat ESCs with both medroxyprogesterone and cAMP stimulated the expression of prolactin (Prl) and decidual/trophoblast prolactin-related protein (Dtprp), while knock-down of Epac1, Epac2 or Rap1 attenuated the expression of these decidual markers. These findings suggest that Epac1, Epac2 and Rap1 play key roles in decidualization.

 

Nothing to Disclose: MY, KK, KT, TD, TT, ET